Etanercept, a soluble tumor necrosis factor (TNF) receptor:Fc fusion protein, was evaluated for safety and efficacy in children with polyarticular juvenile rheumatoid arthritis (JRA) who did not tolerate or had inadequate response to methotrexate. In an open-label phase, 74% of 69 patients showed improvement. In a double-blind trial, 81% of patients receiving placebo withdrew due to disease flare, compared to 28% of those receiving etanercept (P=0.003). The median time to flare was 28 days for placebo and over 116 days for etanercept (P<0.001). No significant differences in adverse events were observed between treatment groups. Etanercept was well tolerated, with no deaths or severe adverse events. It led to significant improvement in disease activity, with 80% of patients showing 30% improvement after seven months of treatment. Etanercept effectively inhibited TNF and lymphotoxin-α, which are involved in JRA pathogenesis. The study confirmed the role of TNF and lymphotoxin-α in JRA and supported the use of etanercept in children with severe polyarticular JRA who did not respond to methotrexate. The results indicate that etanercept is a safe and effective treatment option for children with polyarticular JRA.Etanercept, a soluble tumor necrosis factor (TNF) receptor:Fc fusion protein, was evaluated for safety and efficacy in children with polyarticular juvenile rheumatoid arthritis (JRA) who did not tolerate or had inadequate response to methotrexate. In an open-label phase, 74% of 69 patients showed improvement. In a double-blind trial, 81% of patients receiving placebo withdrew due to disease flare, compared to 28% of those receiving etanercept (P=0.003). The median time to flare was 28 days for placebo and over 116 days for etanercept (P<0.001). No significant differences in adverse events were observed between treatment groups. Etanercept was well tolerated, with no deaths or severe adverse events. It led to significant improvement in disease activity, with 80% of patients showing 30% improvement after seven months of treatment. Etanercept effectively inhibited TNF and lymphotoxin-α, which are involved in JRA pathogenesis. The study confirmed the role of TNF and lymphotoxin-α in JRA and supported the use of etanercept in children with severe polyarticular JRA who did not respond to methotrexate. The results indicate that etanercept is a safe and effective treatment option for children with polyarticular JRA.